The epithelial-to-mesenchymal transition (EMT) is a vital control point in metastatic breast cancer (MBC). TWIST1, SNAIL1, SLUG, and ZEB1, as key EMT-inducing transcription factors (EMT-TFs), are ...involved in MBC through different signaling cascades. This updated meta-analysis was conducted to assess the correlation between the expression of EMT-TFs and prognostic value in MBC patients. A total of 3,218 MBC patients from fourteen eligible studies were evaluated. The pooled hazard ratios (HR) for EMT-TFs suggested that high EMT-TF expression was significantly associated with poor prognosis in MBC patients (HRs = 1.72; 95% confidence intervals (CIs) = 1.53-1.93; P = 0.001). In addition, the overexpression of SLUG was the most impactful on the risk of MBC compared with TWIST1 and SNAIL1, which sponsored fixed models. Strikingly, the increased risk of MBC was less associated with ZEB1 expression. However, the EMT-TF expression levels significantly increased the risk of MBC in the Asian population (HR = 2.11, 95% CI = 1.70-2.62) without any publication bias (t = 1.70, P = 0.11). These findings suggest that the overexpression of potentially TWIST1, SNAIL1 and especially SLUG play a key role in the aggregation of MBC treatment as well as in the improvement of follow-up plans in Asian MBC patients.
MicroRNA-34a (miR-34a) is a master regulator of tumor suppression in breast cancer (BC). This systematic review aims to analyze the diagnostic accuracy of miR-34a in the detection of BC as a ...biomarker.
A total of 1858 BC cases and 494 controls from thirteen eligible studies reported in 9 publications were included. The overall pooled sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), and diagnostic odds ratio (DOR) were 85.50% (95% CI: 83.80-87.00%), 70.00% (95% CI: 65.80-74.10%), 0.29 (95% CI: 0.19-0.43), 2.58 (95% CI: 1.91-3.43), and 9.39 (95% CI: 5.47-16.12), respectively. Similarly, the overall area under the curve (AUC) of the summary receiver operating characteristic (SROC) was 0.80, indicating the high conservation of miR-34a as a biomarker. Furthermore, subgroup analysis suggested that the use of miR-34a as a biomarker is more accurate in tissue-based sample of invasive BC. We also indicated that miR-34a is a capable biomarker in diagnosing BC in people of Caucasian descent.
A systematic search was conducted for eligible publications that address miR-34a expression level in BC cases and noncancerous controls. Diagnostic capacity of miR-34a for BC was assessed using pooled sensitivity and specificity, DOR, and AUC of SROC. PLR and NLR were verified to estimate the miR-34a diagnostic accuracy in clinical level. The quality of the included studies was assessed by QUADAS-2.
These findings suggest miR-34a is a promising non-invasive biomarker in diagnosing BC. Well-designed cohort studies should be implemented to warrant the diagnostic value of miR-34a in clinical purposes.
Background
Nigella sativa
(
N. sativa
) exhibits anti-inflammatory, antioxidant, antidiabetic, antimetastatic and antinociceptive effects and has been used to treat dozens of diseases. Thymoquinone ...(TQ) is an important and active component isolated from
N. sativa
seeds. Inhibition of cancer-associated activating PIK3CA mutations is a new prospective targeted therapy in personalized metastatic breast cancer (MBC). TQ is reported to be an effective inhibitor of the PI3K/Akt1 pathway in MBC. This study aimed to evaluate the in vitro antitumor effect of TQ in the context of two PIK3CA hotspot mutations, p. H1047R and p. H1047L.
Methods and results
Molecular dynamics, free energy landscapes and principal component analyses were also used to survey the mechanistic effects of the p. H1047R and p. H1047L mutations on the PI3K/Akt1 pathway. Our findings clearly confirmed that the p. H1047R and p. H1047L mutants could reduce the inhibitory effect of ΔNp63α on the kinase domain of PIK3CA, resulting in increased activity of PI3K downstream signals. Structurally, the partial disruption of the interaction between the ΔNp63α DNA binding domain and the PIK3CA kinase domain at residues 114–359 and 797–1068 destabilizes the conformation of the activation loop and modifies the PIK3CA/ΔNp63α complex. Alongside these structural changes, we found that TQ treatment resulted in high PI3K/Akt1 pathway inhibition in p. H1047R and p. H1047L-expressing cells versus wild-type cells.
Conclusions
These two PIK3CA hotspot mutations therefore not only contribute to tumor progression in patients with MBC but may also serve as targets for the development of novel small molecule therapeutic strategies.
The escalating misuse and excessive utilization of antibiotics have led to the widespread dissemination of drug-resistant bacteria, posing a significant global healthcare crisis. Of particular ...concern is the increasing prevalence of multi-drug resistant (MDR) opportunistic pathogens in Intensive Care Units (ICUs), which presents a severe threat to public health and contributes to substantial morbidity and mortality. Among them, MDR ESKAPE pathogens account for the vast majority of these opportunistic pathogens. This comprehensive review provides a meticulous analysis of the current prevalence landscape of MDR opportunistic pathogens in ICUs, especially in ESKAPE pathogens, illuminating their resistance mechanisms against commonly employed first-line antibiotics, including polymyxins, carbapenems, and tigecycline. Furthermore, this review explores innovative strategies aimed at preventing and controlling the emergence and spread of resistance. By emphasizing the urgent need for robust measures to combat nosocomial infections caused by MDR opportunistic pathogens in ICUs, this study serves as an invaluable reference for future investigations in the field of antibiotic resistance.
Display omitted
•The urgent prevalence situations of multi-drug resistant (MDR) pathogens.•Diversity and spread of antibiotic resistance determinants in ESKAPE.•Inactivation patterns of the first-line antibiotics driven by pathogens in ICU.•Advanced and combinatorial therapies to control antibiotic resistance.
The worldwide epidemic of metabolic diseases, especially obesity and other diseases caused by it, has shown a dramatic increase in incidence. A great deal of attention has been focused on the ...underlying mechanisms of these pathological processes and potential strategies to solve these problems. Chronic inflammation initiated by abdominal adipose tissues and immune cell activation in obesity is the major cause of the consequent development of complications. In addition to adipocytes, macrophages and monocytes, natural killer (NK) cells have been verified to be vital components involved in shaping the inflammatory microenvironment, thereby leading to various obesity-related metabolic diseases. Here, we provide an overview of the roles of NK cells and the interactions of these cells with other immune and nonimmune cells in the pathological processes of metabolic diseases. Finally, we also discuss potential therapeutic strategies targeting NK cells to treat metabolic diseases.
BRAF and NRAS are the most reported mutations associated to melanomagenesis. The lack of accurate diagnostic markers in response to therapeutic treatment in BRAF/NRAS-driven melanomagenesis is one of ...the main challenges in melanoma personalized therapy. In order to assess the diagnostic value of phosphatidylserine-specific phospholipase A1-alpha (PLA1A), a potent lysophospholipid mediating the production of lysophosphatidylserine, PLA1A mRNA and serum levels were compared in subjects with malignant melanoma (n = 18), primary melanoma (n = 13), and healthy subjects (n = 10). Additionally, the correlation between histopathological subtypes of BRAF/NRAS-mutated melanoma and PLA1A was analyzed. PLA1A expression was significantly increased during melanogenesis and positively correlated to disease severity and histopathological markers of metastatic melanoma. PLA1A mRNA and serum levels were significantly higher in patients with BRAF-mutated melanoma compared to the patients with NRAS-mutated melanoma. Notably, PLA1A can be used as a diagnostic marker for an efficient discrimination between naïve melanoma samples and advanced melanoma samples (sensitivity 91%, specificity 57%, and AUC 0.99), as well as BRAF-mutated melanoma samples (sensitivity 62%, specificity 61%, and AUC 0.75). Our findings suggest that PLA1A can be considered as a potential diagnostic marker for advanced and BRAF-mutated melanoma.
MicroRNA-34a (miR-34a) plays an essential role against tumorigenesis and progression of cancer metastasis. Here, we analyzed the expression, targets and functional effects of miR-34a on epithelial to ...mesenchymal transition-inducing transcription factors (EMT-TFs), such as TWIST1, SLUG and ZEB1/2, and an EMT-inducing protein NOTCH1 in breast cancer (BC) cell migration and invasion and its correlation with tumorigenesis and clinical outcomes. Expression of miR-34a is downregulated in human metastatic breast cancers (MBC) compared to normal breast tissues and is negatively correlated with clinicopathological features of MBC patients. Ectopic expression of miR-34a in MBC cell-line BT-549 significantly inhibits cell migration and invasion, but exhibits no clear effect on BC cell growth. We found that miR-34a is able to inactivate EMT signaling pathway with mediatory of NOTCH1, TWIST1, and ZEB1 upon 3'-UTR activity in MBC cell lines, but has no inhibitory effects on SLUG and ZEB2. Furthermore, we investigated the synergistic effects of Thymoquinone (TQ) and miR-34a together on the expression of EMT-associated proteins. Results showed that co-delivery of miR-34a and TQ is able to inactivate EMT signaling pathway by directly targeting TWIST1 and ZEB1 in BT-549 cell line, indicating that they might be a promising therapeutic combination against breast cancer metastasis. Epigenetic inactivation of the EMT-TFs/miR-34a pathway can potentially alter the equilibrium of these regulations, facilitating EMT and metastasis in BC. Altogether, our findings suggest that miR-34a alone could serve as a potential therapeutic agent for MBC, and together with TQ, their therapeutic potential is synergistically enhanced.
This study aims to explore the predictive noninvasive biomarker for obstructive coronary artery disease (CAD). By using the data set GSE90074, weighted gene co‐expression network analysis (WGCNA), ...and protein–protein interactive network, construction of differentially expressed genes in peripheral blood mononuclear cells was conducted to identify the most significant gene clusters associated with obstructive CAD. Univariate and multivariate stepwise logistic regression analyses and receiver operating characteristic analysis were used to predicate the diagnostic accuracy of biomarker candidates in the detection of obstructive CAD. Furthermore, functional prediction of candidate gene biomarkers was further confirmed in ST‐segment elevation myocardial infarction (STEMI) patients or stable CAD patients by using the datasets of GSE62646 and GSE59867. We found that the blue module discriminated by WGCNA contained 13 hub‐genes that could be independent risk factors for obstructive CAD (P < .05). Among these 13 hub‐genes, a four‐gene signature including neutrophil cytosol factor 2 (NCF2, P = .025), myosin‐If (MYO1F, P = .001), sphingosine‐1‐phosphate receptor 4 (S1PR4, P = .015), and ficolin‐1 (FCN1, P = .012) alone or combined with two risk factors (male sex and hyperlipidemia) may represent potential diagnostic biomarkers in obstructive CAD. Furthermore, the messenger RNA levels of NCF2, MYO1F, S1PR4, and FCN1 were higher in STEMI patients than that in stable CAD patients, although S1PR4 showed no statistical difference (P > .05). This four‐gene signature could also act as a prognostic biomarker to discriminate STEMI patients from stable CAD patients. These findings suggest a four‐gene signature (NCF2, MYO1F, S1PR4, and FCN1) alone or combined with two risk factors (male sex and hyperlipidemia) as a promising prognostic biomarker in the diagnosis of STEMI. Well‐designed cohort studies should be implemented to warrant the diagnostic value of these genes in clinical purpose.
A four‐gene signature (NCF2, MYO1F, S1PR4, and FCN1) alone or combined with two risk factors (male sex and hyperlipidemia) could act as a noninvasive diagnostic biomarker for obstructive coronary artery disease (CAD) and ST‐segment elevation myocardial infarction (STEMI).
To discover vulnerabilities associated with dermokine (DMKN) as a new trigger of the epithelial-mesenchymal transition (EMT) -driven melanoma, we undertook a genome-wide genetic screening using ...transgenic. Here, we showed that DMKN expression could be constitutively increased in human malignant melanoma (MM) and that this correlates with poor overall survival in melanoma patients, especially in BRAF-mutated MM samples. Furthermore, in vitro, knockdown of DMKN inhibited the cell proliferation, migration, invasion, and apoptosis of MM cancer cells by the activation of ERK/MAPK signaling pathways and regulator of STAT3 in downstream molecular. By interrogating the in vitro melanoma dataset and characterization of advanced melanoma samples, we found that DMKN downregulated the EMT-like transcriptional program by disrupting EMT cortical actin, increasing the expression of epithelial markers, and decreasing the expression of mesenchymal markers. In addition, whole exome sequencing was presented with p.E69D and p.V91A DMKN mutations as a novel somatic loss of function mutations in those patients. Moreover, our purposeful proof-of-principle modeled the interaction of ERK with p.E69D and p.V91A DMKN mutations in the ERK-MAPK kinas signaling that may be naturally associated with triggering the EMT during melanomagenesis. Altogether, these findings provide preclinical evidence for the role of DMKN in shaping the EMT-like melanoma phenotype and introduced DMKN as a new exceptional responder for personalized MM therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vasculogenic mimicry (VM) a microvascular system consisting of non-endothelial cells that is newly formed by aggressive tumors, has been proposed as an important therapeutic target in malignant ...melanoma (MM). We performed a systematic literature review to evaluate the diagnostic and prognostic accuracy of VM status for overall survival of MM patients.
The quality of the included studies was evaluated using the QUADAS-2 tool. Diagnostic capacity of VM variables, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under summary receiver operating characteristic (SROC), were pooled using Meta-DiSc software.
A retrospective observational study was conducted based on twelve clinical studies including 978 clinically confirmed melanoma patients with proportion (P). VM+ melanoma cells were associated with poor prognosis in 38% of MM group (P = 0.35, 95% confidence intervals (CI): 0.27-0.42, p < 0.001). The pooled sensitivity and specificity were 0.82 (95% CI: 0.79-0.84) and 0.69 (95% CI: 0.66-0.71), respectively. Furthermore, the pooled PLR, NLR, and DOR were 2.56 (95% CI: 1.94-3.93), 0.17 (95% CI: 0.07-0.42), and 17.75 (95% CI: 5.30-59.44), respectively. Furthermore, the AUC of SROC was 0.63, indicating high reliability of VM status as a biomarker. Importantly, subgroup results suggested that VM+ status is a significantly accurate prognostic biomarker when diagnosed by the CD31-/PAS+ staining methods in Asian MM samples (p < 0.001).
Our findings support the potential of VM status of tumors as a promising prognostic biomarker and emphasize an effective adjuvant therapeutic strategy in the prognosis of Asian MM patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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